Acute Myeloid Leukemia (AML) is a common form of acute leukemia among kids and adults characterized by failure to differentiate and abnormal proliferation of myeloid blasts in the bone marrow (BM). AML is expected to increase as the population ages. Although patients frequently achieve remission after initial treatment with chemotherapy, relapse remains a significant problem. The main cause of relapse and fatal outcome is the development of drug resistance by cancer cells. Recent evidence indicates that leukemic cells become more resistant to treatment due to its interaction with other cells of the so called tumor microenvironment including bone marrow mesenchymal cells (BM-MSCs). One of the molecular hallmarks of resistant AML cells is the increased expression of the oncogene c-Myc. Our preliminary data indicate that nucleophosmin 1 (NPM1), is involved in the biogenesis of microRNAs (miRNAs) especially miR-9 and miR-155 by interacting with Drosha and DiGeorge syndrome critical region 8 (DGCR8), two core components of the miRNA microprocessor complex. We observed that AML cells transfer NPM1 protein to surrounding BM-MSCs within exosomes, leading to increased levels of miR-9 and -155. We also observed that high expression of miR-9, miR-155, c-Myc protein and down-regulation of protein phosphatase 2A (PP2A regulatory (B) subunit B56a {PP2AB56a}, here after simply called PP2A) and glycogen synthase kinase-3 beta (GSK3) protein levels occur in AML cells when co-cultured with BM-MSCs compared to AML cells alone. We hypothesize that AML-educated BM-MSCs transfer miR-9 and miR-155 to AML cells through exosomes. We also hypothesize that miR-9 and miR-155 target PP2A and GSK3, leading to increased c-Myc stability and AML drug resistance. Guided by our preliminary data, we will test the hypothesis in three specific aims: 1) to investigate whether BM-MSCs-derived exosomic miR-9 and miR-155 trafficking affects c-Myc stability in AML cells; 2) to determine whether BM-MSCs-derived exosomic miR-9 and miR-155 affect AML resistance to drugs both in vitro and in vivo; 3) to assess whether inhibitors of exosome secretion restore AML sensitivity to chemotherapy. The proposed research is novel, significant and the approach is innovative. Because it will advance and expand understanding of how exosomic transfer of NPM1 and miR-9, -155 in AML-BM tumor microenvironment can drive resistance. Ultimately, such knowledge has the ability to transform the treatment of AML, increase the survival of leukemia patients and reduce the growing burden on the cancer health care system in the United States.